Sulfur mustard (bis(2-chloroethyl)sulfide; SM) is a vesicant and chemical weapon used in warfare during much of the 20th century, and which remains in the stockpiles of multiple nations today (Syria, Iran, North Korea, Libya, United States, and possibly others). SM exposure affects the eyes, skin, upper airways and lungs. After a brief latent period, respiratory failure and death can develop within 12-48 hours. Despite a century of study, the mechanisms responsible for SM's toxic effects remain unsolved, and clinically effective rescue therapies or antidotes are not available.
Initial reports of human SM inhalation toxicity in the early 1900s described the presence of airway obstructive necrotic debris/mucosa, or ‘pseudomembranes’, in the large airways of victims, and these were more recently confirmed in the victims of the Iran-Iraq war (Eisenmenger, W. et al., 1991, J Forensic Sci 36:1688-1698; Willems, J. L., 1989, Ann Med Milit Belg 3S:1-61). Severe such lesions have been reported lead to respiratory compromise with need for artificial ventilation, and death in 80% of those needing intubation (Willems, J. L., 1989, Ann Med Milit Belg 3S:1-61). Further, chronic conducting airway lesions, such as bronchiolitis obliterans, tracheal/bronchial stenosis and chronic bronchitis, are commonly found in SM inhalation survivors months to years after exposure (Willems, J. L., 1989, Ann Med Milit Belg 3S:1-61; Ghanei, M. et al., 2008, Respir Med 102:825-830), while chronic alveolar or parenchymal injury is less frequent. Therefore, airway injury predominates during both the acute, as well as the chronic phases of SM-induced lung injury.
Airway obstruction from fibrin casts represents one form of a disorder commonly referred to as plastic bronchitis. This is a rare condition characterized by formation of branching bronchial casts that partially or completely obstruct the tracheobronchial tree, often leading to life-threatening respiratory failure. Even though inhalation of chemicals like sulfur mustard can lead to the development of plastic bronchitis, it can also occur due to causes other than chemical inhalation. While occasionally seen in adults (Watanabe, K. et al., 2008, Intern Med 47:1549; Eberlein, M. H. et al., 2008, Am J Med Sci 335:163-169), plastic bronchitis not due to chemical inhalation is a disorder affecting mostly children. It can develop after Fontan surgery for congenital cyanotic heart diseases (Goo, H. W. et al., 2008, Pediatr Radiol 38:989-993; Do, T. B. et al., 2009, Pediatr Cardiol 30:352-355; Costello, J. M. et al., Pediatrics 109:e67; Heath, L. et al., 2011, Pediatr Cardiol 32:1182-1189; Wakeham, M. K. et al., 2005, Pediatr Crit Care Med 6:76-78; Brogan, T. V. et al., 2002, Pediatr Pulmonol 34:482-487; Seear, M. et al., 1997, Am J Respir Crit Care Med 155:364-370), or after various bronchopulmonary diseases such as asthma (Tonan, M. et al., 2011, J Anesth; Pawar, S. S. et al., 2011, Ann Otol Rhinol Laryngol 120:697-699), cystic fibrosis (Mateos-Corral, D. et al., 2009, Pediatr Pulmonol 44:939-940; Waring, W. W. et al., 1967, Pediatrics 39:166-175), acute chest syndrome of sickle cell disease (Moser, C. et al., 2001, Chest 120:608-613), viral lower respiratory tract infections including H1N1 (Deng, J. et al., 2010, Chest 138:1486-1488), neoplasms such as lymphoma (Kuperman, T. et al., 2006, Pediatr Pulmonol 41:893-896), chemical or thermal inhalation injuries (Eberlein, M. H. et al., 2008, Am J Med Sci 335:163-169; Pruitt, B. A., Jr., 1974, Clin Plast Surg 1:667-691; Cox, R. A. et al., 2003, Am J Respir Cell Mol Biol 29:295-302; Veress, L. A. et al., 2010, Am J Respir Crit Care Med 182:1352-1361) or idiopathic causes (Krenke, K. et al., 2010, Respiration 80:146-147). Presenting symptoms include wheezing, coughing, expectoration of rubbery casts, chest pain, hypoxemia, and/or frank respiratory distress (Brogan, T. V. et al., 2002, Pediatr Pulmonol 34:482-487; Madsen, P. et al., 2005, Paediatr Respir Rev 6:292-300). Examination of patients with plastic bronchitis, regardless of etiology, reveals wheezing or absent breath sounds over affected regions, while chest radiographs can show segmental lung collapse, or bilateral patchy consolidations often misdiagnosed as pneumonia (Madsen, P. et al., 2005, Paediatr Respir Rev 6:292-300). Diagnosis is made either by a history of cast expectoration, or by bronchoscopic or chest CT findings of casts within airways (Eberlein, M. H. et al., 2008, Am J Med Sci 335:163-169; Goo, H. W. et al., 2008, Pediatr Radiol 38:989-993). Mortality from plastic bronchitis occurs due to respiratory failure related to central airway obstruction, and is more severe in those with underlying cardiac abnormalities (mortality rate of 44-60%) (Brogan, T. V. et al., 2002, Pediatr Pulmonol 34:482-487; Madsen, P. et al., 2005, Paediatr Respir Rev 6:292-300; Zahorec, M. et al., 2009, Pediatr Crit Care Med 10:e34-36).
Treatment of plastic bronchitis, regardless of etiology, has been based primarily on anecdotal evidence reported from individual affected patients. Previously tried medications have included inhaled or systemic corticosteroids (Wang, G. et al., 2006, Acta Pharmacol Sin 27:1206-1212), mucolytics (Eberlein, M. H. et al., 2008, Am J Med Sci 335:163-169), antibiotics (Shinkai, M. et al., 2005, Paediatr Respir Rev 6:227-235), pulmonary vasodilators (Haseyama, K. et al., 2006, J Thorac Cardiovasc Surg 132:1232-1233), and anticoagulants such as heparin (Desai, M. H. et al., 1998, J Burn Care Rehabil 19:210-212). Non-pharmaceutical treatments have included cast removal via bronchoscopy (Silva, R. C. et al., 2011, Arch Otolaryngol Head Neck Surg 137:401-403), vest therapy, fenestration of the Fontan circuit (Wilson, J. et al., 2005, Pediatr Cardiol 26:717-719), thoracic duct ligation (Shah, S. S. et al., 2006, Ann Thorac Surg 81:2281-2283), AV synchronization (Barber, B. J. et al., 2004, Pediatr Cardiol 25:73-76), ECMO (Tonan, M. et al., 2011, J Anesth), and heart transplantation for severe cardiac patients (Laubisch, J. E. et al., 2011, Pediatr Cardiol 32:1193-1195).
As noted above, SM inhalation is one cause of the rare but life-threatening disorder of plastic bronchitis, characterized by bronchial cast formation, resulting in severe airway obstruction that can lead to respiratory failure and death. Mortality in those requiring intubation is >80%. To date, no antidote exists for sulfur mustard toxicity. Additionally, therapies for plastic bronchitis are solely anecdotal, due to lack of systematic research available to assess drug efficacy in improving mortality and/or morbidity.